Deletion of GIT1 Impacts eNOS Activity To Aggravate sFlt-1–Induced Preeclampsia Phenotype in Mice

Zhang, Shenghong; Zou, Cuili; Zhang, Qiaoqin

doi:10.1534/g3.118.200509

Cited by 4 publications

(4 citation statements)

References 37 publications

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“…GIT1, a GTPase-activating protein, plays a crucial role in regulating the biological activity of endothelial nitric oxide synthase (eNOS) [ 68 ]. The absence of GIT1 seems to aggravate PE-like phenotypes in mice by impeding NO production through suppression of eNOS activity [ 69 ].…”

Section: Pathogenesis Of Preeclampsiamentioning

confidence: 99%

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

et al. 2020

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Preeclampsia (PE) is a serious pregnancy complication, affecting about 5–7% of pregnancies worldwide and is characterized by hypertension and damage to multiple maternal organs, primarily the liver and kidneys. PE usually begins after 20 weeks’ gestation and, if left untreated, can lead to serious complications and lifelong disabilities—even death—in both the mother and the infant. As delivery is the only cure for the disease, treatment is primarily focused on the management of blood pressure and other clinical symptoms. The pathogenesis of PE is still not clear. Abnormal spiral artery remodeling, placental ischemia and a resulting increase in the circulating levels of vascular endothelial growth factor receptor-1 (VEGFR-1), also called soluble fms-like tyrosine kinase-1 (sFlt-1), are believed to be among the primary pathologies associated with PE. sFlt-1 is produced mainly in the placenta during pregnancy and acts as a decoy receptor, binding to free VEGF (VEGF-A) and placental growth factor (PlGF), resulting in the decreased bioavailability of each to target cells. Despite the pathogenic effects of increased sFlt-1 on the maternal vasculature, recent studies from our laboratory and others have strongly indicated that the increase in sFlt-1 in PE may fulfill critical protective functions in preeclamptic pregnancies. Thus, further studies on the roles of sFlt-1 in normal and preeclamptic pregnancies are warranted for the development of therapeutic strategies targeting VEGF signaling for the treatment of PE. Another impediment to the treatment of PE is the lack of suitable methods for delivery of cargo to placental cells, as PE is believed to be of placental origin and most available therapies for PE adversely impact both the mother and the fetus. The present review discusses the pathogenesis of PE, the complex role of sFlt-1 in maternal disease and fetal protection, and the recently developed placenta-targeted drug delivery system for the potential treatment of PE with candidate therapeutic agents.

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Section: Pathogenesis Of Preeclampsiamentioning

confidence: 99%

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

et al. 2020

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“…4 The activity of eNOS is regulated by varieties of factors including post-translational phosphorylation, eNOS coupling, and the interaction of proteins. 5 Our previous studies indicated that low androgen status inhibited eNOS phosphorylation in corpus cavernosum of rats resulting in decreased NO production and impaired erectile function. 6 eNOS dimer formed by the coupling of eNOS monomer produces NO relaxing smooth muscle cells, while the uncoupling of eNOS produces superoxide radical (O 2 − ).…”

Section: Introductionmentioning

confidence: 98%

“…Nitric oxygen (NO) catalyzed by eNOS in endothelial cells plays a vital role in the initiation and maintenance of penile erection 4 . The activity of eNOS is regulated by varieties of factors including post‐translational phosphorylation, eNOS coupling, and the interaction of proteins 5 . Our previous studies indicated that low androgen status inhibited eNOS phosphorylation in corpus cavernosum of rats resulting in decreased NO production and impaired erectile function 6 .…”

Section: Introductionmentioning

confidence: 99%

Low androgen status inhibits erectile function by inducing eNOS uncoupling in rat corpus cavernosum

et al. 2020

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Background The number of erectile dysfunction (ED) patients is increasing annually. How to improve the effectiveness of ED treatment is an important issue for the field of andrology. Objectives To investigate whether low androgen status impairs the erectile function of rats by regulated endothelial nitric oxide synthase (eNOS) uncoupling. Materials and methods Thirty‐six 8‐week‐old male Sprague Dawley (SD) rats were randomly divided into six groups as follows: 4‐week sham‐operated group (4w‐sham), 4‐week castration group (4w‐cast), 4‐week castration + testosterone (T) group (4w‐cast + T), 8‐week sham‐operated group (8w‐sham), 8‐week castration group (8w‐cast), and 8‐week castration + T group (8w‐cast + T). Three mg/kg of T was subcutaneously injected every other day in castration + T groups. The ratio of the maximum intracavernous pressure/the mean arterial pressure (ICPmax/MAP), the level of serum T, dihydrobiopterin(BH2), tetrahydrobiopterin (BH4), nitric oxygen(NO), 3‐nitrotyrosine(3NT), dihydrofolate reductase (DHFR), guanosine triphosphate cyclohydrolase 1 (GTPCH1), nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), and eNOS monomers/dimers in the corpus cavernosum were detected. Results The ratio of ICPmax/MAP and BH4/BH2, the level of serum T, NO, and GTPCH1 decreased significantly in castration groups compared with sham‐operated groups and castration + T groups (P < .05) and decreased significantly in 8w‐cast group compared with 4w‐cast group (P < .05). The expression of 3NT and NOX2 and the ratio of eNOS monomers/dimers increased significantly in castration groups compared with sham‐operated groups and castration + T groups (P < .01) and increased significantly in 8w‐cast group compared with 4w‐cast group (P < .01). The expression of DHFR in 4w‐cast group was significantly higher than that in 4w‐sham group and 4w‐cast + T group (P < .01) and in 8w‐cast group was significantly lower than that in 8w‐sham group and 8w‐cast + T group (P < .01). Discussion and Conclusion Low androgen status induces eNOS uncoupling by reducing BH4/BH2 and increasing 3NT. Due to the decreased NO production, the erectile function of the rats was impaired.

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“… 15 In a rat model of preeclampsia, GIT1 knockdown can inhibit the activity of eNOS in the placenta and induce the exacerbation of the preeclampsia phenotype. 16 In a rat model of hepatic sinusoidal vascular endothelial injury, the expression level of GIT1 in vascular endothelial cells is decreased; the interaction between GIT1 and eNOS is weakened; and the activity of eNOS and the expression of NO is decreased. However, upregulation of GIT1 in damaged hepatic sinusoidal vascular endothelial cells can directly activate eNOS and considerably increase NO expression.…”

Section: Introductionmentioning

confidence: 99%

Low testosterone state inhibits erectile function by downregulating the expression of GIT1 in rat penile corpus cavernosum

Zhu

Zhao

et al. 2023

Sexual Medicine

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Background The mechanism of erectile dysfunction (ED) caused by a low androgen level is still not clear. Aim To explore the influence of the low testosterone state on G protein–coupled receptor kinase interactor 1 (GIT1) and its contact to erectile function. Methods Thirty male Sprague-Dawley rats aged 8 weeks were distributed at random into 5 groups: control (sham operated), castration, testosterone supplement after castration, castration + vacant lentiviral transfection, and castration + lentiviral transfection. The testis and epididymis were removed through a scrotal incision to develop castrated rats. Four weeks after castration, a lentivirus carrying the GIT1 gene was injected into the middle of rat penile corpus cavernosum. One week after transfection, maximum intracavernous pressure/mean arterial pressure (ICPmax/MAP), serum testosterone, nitric oxide, GIT1, endothelial nitric oxide synthase (eNOS), phospho-eNOS (p-eNOS), p-eNOS/eNOS, and the interaction between eNOS and GIT1 were assessed in the rats. Outcomes The levels of GIT1 in the penile cavernous tissue of castrated rats are significantly lower than that of controls. Results GIT1 was expressed in the cytoplasm and cell membrane of vascular endothelial cells and smooth muscle cells in rat penile tissue. In comparison with normal rats, the castrated rats showed lower levels of GIT1 expression, GIT1 and eNOS interaction, p-eNOS/eNOS, nitric oxide, and ICPmax/MAP (P < .01). Overexpression of GIT1 can intensively enhance the expression level of GIT1, the interaction between GIT1 and eNOS, p-eNOS/eNOS, nitric oxide, and ICPmax/MAP in rats (P < .01). Clinical Translation Modulating the interaction between eNOS and GIT1 might be a novel method of treating ED caused by a low androgen level. Strengths and Limitations The impact of GIT1 phosphorylation on the activity of eNOS and its possible mechanisms affecting erectile function require further study. Conclusion A low testosterone state inhibits erectile function in rats by reducing the expression of GIT1 and the protein interaction between GIT1 and eNOS.

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Deletion of GIT1 Impacts eNOS Activity To Aggravate sFlt-1–Induced Preeclampsia Phenotype in Mice

Cited by 4 publications

References 37 publications

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

Low androgen status inhibits erectile function by inducing eNOS uncoupling in rat corpus cavernosum

Low testosterone state inhibits erectile function by downregulating the expression of GIT1 in rat penile corpus cavernosum

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